Reversed biaryl spiroaminooxazoline analogues as alpha2c adrenergic receptor modulators

Abstract

In its many embodiments, the present invention provides a novel class of biaryl spiroaminooxazoline analogues as modulators of α2C adrenergic receptor agonists, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the α2C adrenergic receptors using such compounds or pharmaceutical compositions.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to reverse biaryl spiroaminooxazoline analogues useful as alpha-2C (or “α2C”) adrenergic receptor modulators, methods for making these compounds, pharmaceutical compositions containing the compounds, and methods of treatment and prevention using the compounds and compositions to treat disease states associated with the modulation of the alpha-2C receptor, such as congestion (including nasal), migraine, congestive heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontinence, Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, pain and psychotic disorders (e.g., depression and schizophrenia).BACKGROUND OF THE INVENTION

[0002] The initial classification of adrenergic receptors into α- and β-families was first described by Ahlquist in 1948 (Ahlquist RP, “A Study of the Adrenergic Receptors,” Am. J. Physiol. 153:586-600 (1948)). Functionally, the α-adrenergic receptors were shown to ...

Examples

example 1

Preparative Example 1

[0433]

Step 1

[0434]5-Bomo-tetralone 1A (30 g, 134 mmol) in DCM (200 mL) was added TMSCN (20 mL, 1.2 equiv. 160 mmol) at 0° C. followed by AlCl3 (3 g, 0.2 equiv., 26 mmol). The reaction was stirred at r.t. for 1 hr before been diluted with EtOAc (500 mL), washed with aq. NaOH (200 mL) and brine (100 mL). The organic layer was dried with Na2SO4, concentrated by rotavap and chromatographed (0% to 40% EtOAc / Hexane) to give the desired product 1B (37.4 g, 86%).

Step 2

[0435]Compound 1B (37.4 g, 116 mmol) in THF (300 mL) at 0° C. was added LAH (150 mL, 1.0M in Et2O, 150 mmol). The reaction was stirred at 0° C. for 0.5 hr before quenched by adding water dropwise until no gas was released: The reaction was then added aq. NaOH (1.0 M, 150 mL) and extracted with DCM thoroughly. The organic layer was separated, dried with Na2SO4 and concentrated. The crude (1C, 30 g, 99%) was used in the next step without further purification.

Step 3

[0436]A solution of 1C (1.3 g, 5.4 mmol) in ...

example 2

Preparative Example 2

[0439]

Step 1

[0440]To a solution of compound 1B (650 mg, 2 mmol) in anhydrous THF (3 mL) was added MeMgBr (2.2 mL, 1.1 equiv., 2.2 mmol) at 0° C. The reaction was stirred at RT overnight before cooled to 0° C. A solution of NaBH4 in methanol (2 mL) was added and the reaction was further stirred at r.t. for 4 hr. Aq. HCl solution was added followed by stirring for another 1 hr. Aq. NaOH was added to make the pH around 9, and the reaction was extracted with DCM thoroughly. The organic layer was dried with Na2SO4 and concentrated to give the crude 2A which was used without further purification.

Step 2

[0441]To a solution of 2A (230 g, 1 mmol) in ethanol (3 mL) was added BrCN (0.4 mL, 5.0 M in CH3CN, 2.0 mmol) and the reaction was stirred at RT overnight. The mixture was diluted with aq. NaOH (1.0M, 10 mL) and extracted with DCM. The layers were separated. The combined organic layers were dried over Na2SO4, concentrated and chromatographed (2-5% of NH3-MeOH / DCM) to giv...

example 3

Preparative Example 3

[0443]

Step 1

[0444]

[0445]A solution of 5-bromo-tetralone (2.25 g, 10.0 mmol) in THF (100 mL) was cooled in an ice-H2O bath and a solution of allymagnesium bromide in THF (1.0M, 50 mL, 50 mmol) was added via a dropping funnel over a period of 25 min; stirring was continued at 0° C. for ½ h, then at RT for 16 h. NH4Cl (Sat., 100 mL) and EtOAc (200 mL) were added, the aqueous was extracted once more with EtOAc (100 mL). The combined organic was washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc-Hexane (1:10) to obtain 3A as a yellow syrup. (2.28 g).

Step 2

[0446]

[0447]A solution of 3A (1.2 g, 4.50 mmol) in mixed solvent (15 mL CH2Cl2 and 7.5 mL MeOH) was cooled in a dry ice—acetone bath. Ozone was bubbled into it at a rate of 1.5 / min for 10 min and the solution turned blue. Oxygen was then blown into the mixture, followed by the addition of dimethyl sulfide...

FIELD OF THE INVENTION

[0001] The present invention relates to reverse biaryl spiroaminooxazoline analogues useful as alpha-2C (or “α2C”) adrenergic receptor modulators, methods for making these compounds, pharmaceutical compositions containing the compounds, and methods of treatment and prevention using the compounds and compositions to treat disease states associated with the modulation of the alpha-2C receptor, such as congestion (including nasal), migraine, congestive heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontinence, Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, pain and psychotic disorders (e.g., depression and schizophrenia).BACKGROUND OF THE INVENTION

[0002] The initial classification of adrenergic receptors into α- and β-families was first described by Ahlquist in 1948 (Ahlquist RP, “A Study of the Adrenergic Receptors,” Am. J. Physiol. 153:586-600 (1948)). Functionally, the α-adrenergic receptors were shown to ...

Examples

example 1

Preparative Example 1

[0433]

Step 1

[0434]5-Bomo-tetralone 1A (30 g, 134 mmol) in DCM (200 mL) was added TMSCN (20 mL, 1.2 equiv. 160 mmol) at 0° C. followed by AlCl3 (3 g, 0.2 equiv., 26 mmol). The reaction was stirred at r.t. for 1 hr before been diluted with EtOAc (500 mL), washed with aq. NaOH (200 mL) and brine (100 mL). The organic layer was dried with Na2SO4, concentrated by rotavap and chromatographed (0% to 40% EtOAc / Hexane) to give the desired product 1B (37.4 g, 86%).

Step 2

[0435]Compound 1B (37.4 g, 116 mmol) in THF (300 mL) at 0° C. was added LAH (150 mL, 1.0M in Et2O, 150 mmol). The reaction was stirred at 0° C. for 0.5 hr before quenched by adding water dropwise until no gas was released: The reaction was then added aq. NaOH (1.0 M, 150 mL) and extracted with DCM thoroughly. The organic layer was separated, dried with Na2SO4 and concentrated. The crude (1C, 30 g, 99%) was used in the next step without further purification.

Step 3

[0436]A solution of 1C (1.3 g, 5.4 mmol) in ...

example 2

Preparative Example 2

[0439]

Step 1

[0440]To a solution of compound 1B (650 mg, 2 mmol) in anhydrous THF (3 mL) was added MeMgBr (2.2 mL, 1.1 equiv., 2.2 mmol) at 0° C. The reaction was stirred at RT overnight before cooled to 0° C. A solution of NaBH4 in methanol (2 mL) was added and the reaction was further stirred at r.t. for 4 hr. Aq. HCl solution was added followed by stirring for another 1 hr. Aq. NaOH was added to make the pH around 9, and the reaction was extracted with DCM thoroughly. The organic layer was dried with Na2SO4 and concentrated to give the crude 2A which was used without further purification.

Step 2

[0441]To a solution of 2A (230 g, 1 mmol) in ethanol (3 mL) was added BrCN (0.4 mL, 5.0 M in CH3CN, 2.0 mmol) and the reaction was stirred at RT overnight. The mixture was diluted with aq. NaOH (1.0M, 10 mL) and extracted with DCM. The layers were separated. The combined organic layers were dried over Na2SO4, concentrated and chromatographed (2-5% of NH3-MeOH / DCM) to giv...

example 3

Preparative Example 3

[0443]

Step 1

[0444]

[0445]A solution of 5-bromo-tetralone (2.25 g, 10.0 mmol) in THF (100 mL) was cooled in an ice-H2O bath and a solution of allymagnesium bromide in THF (1.0M, 50 mL, 50 mmol) was added via a dropping funnel over a period of 25 min; stirring was continued at 0° C. for ½ h, then at RT for 16 h. NH4Cl (Sat., 100 mL) and EtOAc (200 mL) were added, the aqueous was extracted once more with EtOAc (100 mL). The combined organic was washed with brine (100 mL), dried over anhydrous MgSO4, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc-Hexane (1:10) to obtain 3A as a yellow syrup. (2.28 g).

Step 2

[0446]

[0447]A solution of 3A (1.2 g, 4.50 mmol) in mixed solvent (15 mL CH2Cl2 and 7.5 mL MeOH) was cooled in a dry ice—acetone bath. Ozone was bubbled into it at a rate of 1.5 / min for 10 min and the solution turned blue. Oxygen was then blown into the mixture, followed by the addition of dimethyl sulfide...

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